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Note that this prospective cohort study demonstrated an association with depressive symptoms and faster cognitive decline in the elderly.

Be aware that autopsy of brain tissue from decedents did not reveal an association between depression and specific pathologic changes in the brain.

Depression was associated with cognitive impairment in a cohort of elderly individuals but not with specific brain abnormalities that underlie most dementias, researchers said.

Among nearly 1,800 participants in the Religious Orders Study and Rush Memory and Aging Project followed for a mean of 7.8 years, the occurrence and severity of depression was unrelated to the level of brain pathology, such as Alzheimer's disease-related depositions and cerebral infarcts, seen subsequently at autopsy in those who died, according to Robert S. Wilson, PhD, of Rush University in Chicago, and colleagues.

About half the cohort developed mild cognitive impairment during follow-up and 18% were diagnosed with dementia, and these individuals did have a greater burden of depressive symptoms prior to diagnosis, the researchers reported online in Neurology.

But in a mixed-effects statistical model that adjusted for brain pathology markers, the level of depressive symptoms accounted for only 4.4% of the remaining variability in cognitive decline, they noted.

In effect, the findings suggest that depression may promote cognitive decline in the elderly, whereas age-related brain pathologies leading to dementia probably do not cause depression.

From a patient management perspective, the message is that "interventions targeting depressive symptoms and psychological distress have the potential to help maintain cognitive health in old age," Wilson and colleagues concluded.

David Knopman, MD, of the Mayo Clinic in Rochester, Minn., told MedPage Today that this was "an extremely strong study" that should help clinicians sharpen their treatment of older patients showing signs of both depression and cognitive impairment.

Knopman, who was not involved with the study but had reviewed it for Neurology, said it suggests that depression treatment would not be futile in this population, since the depressive symptoms were not related to the neuropathologies that underlie cognitive decline.

Associations between depression and cognitive impairment have been found in numerous prior studies, but whether they are linked causally hasn't been clear. Wilson and colleagues noted that the possibility of cognitive decline causing depression has not received much support from clinical data, but other explanations have not been explored systematically.

In particular, the researchers wanted to examine whether cognitive decline and depression may spring from the same underlying neuropathology, versus some other independent association.

For this attempt, they analyzed data from two ongoing cohort studies centered at Rush, in which participants undergo annual clinical exams and agree to donate their brains after death for post-mortem analysis. All were cognitively normal at baseline; their mean age was 77 and, for those dying during follow-up, the mean age at death was 88.

There were 1,764 participants in both cohorts, including 582 who died during follow-up and whose brains were examined for pathological markers. Besides tau tangles and beta-amyloid plaques, the investigators quantified neocortical Lewy bodies, hippocampal sclerosis, and cerebral infarcts of all sizes.

The Mini-Mental State Examination (MMSE) was used to assess cognitive function. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression (CES-D) Scale, which gives patients one point for each of 10 symptoms that they endorse.

At enrollment, 963 of the 1,764 cohort members had no depressive symptoms, 371 had one, 171 had two, 113 had three, 64 had four, and the remaining 82 had five or more, the researchers reported. Over time during follow-up, the likelihood of having no depressive symptoms dropped slowly, to just under 50% after 8 years in the full sample and to about 35% at death in the subgroup who died.

In the post-mortem group, none of the measures of brain pathology were significantly associated with changes in CES-D scores over time or with the score obtained at the last exam prior to death. Such pathology was not uncommon: 32% of the group had large infarcts, 28% had at least one chronic microinfarct, 12% showed Lewy bodies, and 6% had hippocampal sclerosis. Levels of beta-amyloid plaque and tau tangles were also similar to those expected in individuals in their 70s and 80s.

This finding, Wilson and colleagues indicated, argues against the possibility that depressive symptoms stem from these types of physical neuropathologies.

The researchers did, however, find that average CES-D scores during follow-up correlated inversely with changes in MMSE scores -- that is, higher mean depression score was significantly associated with faster cognitive decline (P<0.001). Wilson and colleagues described it as a dose-response relationship: as mean CES-D scores increased, the mean rate of decline in MMSE score also increased.

The association between CES-D and MMSE scores remained significant even after adjustments for the neuropathological markers, the researchers said.

What the study still did not determine, though, was the mechanism(s) by which depression may promote or accelerate cognitive decline, Wilson and colleagues noted.

They acknowledged that the answer may lie in brain structure changes not evaluated in the study, such as atrophy in emotion-regulating regions and defects in white matter integrity, as well as abnormalities at the cellular level in these regions.

Limitations cited by the authors included the volunteer nature of the study, lack of data on cerebrovascular disease and some other clinical characteristics, and the brief self-report used to assess depression symptoms.

The study was funded by the National Institute on Aging and the Illinois Department of Public Health.

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